Healthy
Conditions
Keywords
long-acting beta agonist (LABA), corticosteroid, pMDI, inhaler
Brief summary
The purpose of this study is to test the body's response to several doses of two different inhalation products in healthy volunteers.
Detailed description
Healthy subjects will be enrolled and will receive 2, 6, and 12 inhalations from both the test and reference pMDI products according to a six-period cross-over design. Electrocardiograms (ECGs) and plasma potassium and glucose levels will be measured pre-dose and over 6 hours post-dose.
Interventions
DRUGSalmeterol
A, D 2 puffs; B, E 6 puffs; C, F 12 puffs
DRUGfluticasone propionate
A, D 2 puffs; B, E 6 puffs; C, F 12 puffs
Sponsors
Kindeva Drug Delivery
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Volunteer * Willing and able to give informed consent * Willing to withhold all alcoholic beverages for 48 hours and all xanthine- containing foods and beverages for 24 hours prior to reporting to clinic * Male and female subjects aged 18 to 55 years (inclusive) * Subjects must agree to use an adequate method of contraception from admission through 12 weeks after last administration
Exclusion criteria
* Evidence or history of clinically significant abnormalities or disease or chronic respiratory disorders * Any presence or history of a clinically significant allergy including any adverse reaction to study drug * History of drug or alcohol abuse within the past 2 years * Smoked tobacco within the past 6 months or have a history of more than 10- pack years (number of packs smoked per day x number of years smoked) * Donation or loss of greater than 400 mL of blood within the previous 3 months * Have received any prescription medication within 4 weeks or investigational medication within 12 weeks of study (exception: contraceptives are permitted) * Have received any non-prescription medication within 14 days prior to dosing (exception: paracetamol use within 2 days) * Upper respiratory tract infection (excluding otitis media) within 14 days of the first study day, or lower respiratory tract infection within the last 3 months * If female, nursing, lactating or pregnant * Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine) * Surgery scheduled during the study or within 3 weeks after last dose * History of familial long QT syndrome or history of sudden death in family members aged \< 30 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Potency Max Heart Rate | Baseline, up to 6 hrs | Selection of steepest part of dose response curve for Relative Potency: 6 and 12 inhalation dose pairs. Slope of B and C line compared with slope of E and F to obtain relative potency value. Two inhalation dose not utilized as not on steepest part of curve. |
| Relative Potency QTcB Interval | Baseline up to 6 hrs | Selection of steepest part of dose response curve for Relative Potency: 2 and 6 inhalation dose pairs. Slope of A and B line compared with slope of D and E to obtain relative potency value. Twelve inhalation dose not utilized as not on steepest part of curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Max QTcB | Baseline through 6 hours | For each dose, the 95% CIs for the mean difference for the test product versus the reference product were calculated. |
| Max Heart Rate | Baseline through 6 hours | max heart rate at the 2, 6, or 12 inhalations dose, assessed at multiple times over 6 hours |
| Plasma Potassium Level | baseline through 6 hours | maximum plasma levels of potassium at 2, 6 or 12 inhalations dose inhalations dose, assessed a multiple times over 6 hours. |
| Max Plasma Glucose Level | baseline through 6 hours | maximum levels of glucose at the 2, 6 or 12 inhalations dose, assessed at multiple times over 6 hours. |
Countries
United Kingdom
Participant flow
Recruitment details
Recruitment began 07 July 2014
Participants by arm
| Arm | Count |
|---|---|
| All Subjects salmeterol and fluticasone propionate | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | poor inhalation technique | 0 | 1 | 0 | 0 | 0 | 2 |
| Overall Study | protocol stop criteria | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 33.5 years STANDARD_DEVIATION 10.8 |
| BMI | 23.6 kg/m2 STANDARD_DEVIATION 1.8 |
| forced expiratory volume at one second | 101.19 % predicted normal STANDARD_DEVIATION 10.74 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 46 Participants |
| Region of Enrollment United Kingdom | 52 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 49 | 5 / 48 | 11 / 47 | 5 / 47 | 4 / 48 | 8 / 50 |
| other Total, other adverse events | 4 / 49 | 5 / 48 | 11 / 47 | 5 / 47 | 4 / 48 | 8 / 50 |
| serious Total, serious adverse events | 0 / 49 | 0 / 48 | 0 / 47 | 0 / 47 | 0 / 48 | 0 / 50 |
Outcome results
Primary
Relative Potency Max Heart Rate
Selection of steepest part of dose response curve for Relative Potency: 6 and 12 inhalation dose pairs. Slope of B and C line compared with slope of E and F to obtain relative potency value. Two inhalation dose not utilized as not on steepest part of curve.
Time frame: Baseline, up to 6 hrs
Population: relative potency calculated for dose pairs B (6 inhalations) and C (12 inhalations), compared with E (6 inhalations) and F (12 inhalations)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Test B and C vs Reference E and F | Relative Potency Max Heart Rate | 0.8619 unitless |
Comparison: The measurement of relative potency was conducted for the pair of doses which met the above criteria and lay on the steepest linear portion of the dose response curve. The log estimate of relative potency was obtained as the ratio of the estimated treatment effect as measured by the difference in the intercepts of the parallel lines divided by the estimate of the common slope for log dose.p-value: >0.190% CI: [0.67, 1.5]ANOVA
Primary
Relative Potency QTcB Interval
Selection of steepest part of dose response curve for Relative Potency: 2 and 6 inhalation dose pairs. Slope of A and B line compared with slope of D and E to obtain relative potency value. Twelve inhalation dose not utilized as not on steepest part of curve.
Time frame: Baseline up to 6 hrs
Population: relative potency calculated for dose pairs A (2 inhalations) and B (6 inhalations), compared with D (2 inhalations) and E (6 inhalations)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Test B and C vs Reference E and F | Relative Potency QTcB Interval | 1.0760 unitless |
Comparison: The measurement of relative potency was conducted for the pair of doses which met the above criteria and lay on the steepest linear portion of the dose response curve. The log estimate of relative potency was obtained as the ratio of the estimated treatment effect as measured by the difference in the intercepts of the parallel lines divided by the estimate of the common slope for log dose.p-value: >0.190% CI: [0.67, 1.5]ANOVA
Secondary
Max Heart Rate
max heart rate at the 2, 6, or 12 inhalations dose, assessed at multiple times over 6 hours
Time frame: Baseline through 6 hours
Population: subjects who received the test and the reference product at the 2, 6, or 12 inhalations dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test B and C vs Reference E and F | Max Heart Rate | 65.1 bpm | Standard Deviation 10.9 |
| Reference Product D | Max Heart Rate | 65.5 bpm | Standard Deviation 10.1 |
| Test Product B | Max Heart Rate | 68.9 bpm | Standard Deviation 11 |
| Reference Product E | Max Heart Rate | 69.9 bpm | Standard Deviation 12.2 |
| Test Product C | Max Heart Rate | 75.3 bpm | Standard Deviation 13.3 |
| Reference Product F | Max Heart Rate | 76.8 bpm | Standard Deviation 14.8 |
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.5595% CI: [-2.5, 1.4]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.5395% CI: [-2.5, 1.3]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.01195% CI: [-2.5, 1.3]ANOVA
Secondary
Max Plasma Glucose Level
maximum levels of glucose at the 2, 6 or 12 inhalations dose, assessed at multiple times over 6 hours.
Time frame: baseline through 6 hours
Population: subjects who received both the test and reference products at the two inhalations dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test B and C vs Reference E and F | Max Plasma Glucose Level | 5.31 mmol/L | Standard Deviation 0.49 |
| Reference Product D | Max Plasma Glucose Level | 5.31 mmol/L | Standard Deviation 0.4 |
| Test Product B | Max Plasma Glucose Level | 5.53 mmol/L | Standard Deviation 0.65 |
| Reference Product E | Max Plasma Glucose Level | 5.62 mmol/L | Standard Deviation 0.54 |
| Test Product C | Max Plasma Glucose Level | 5.88 mmol/L | Standard Deviation 0.66 |
| Reference Product F | Max Plasma Glucose Level | 5.98 mmol/L | Standard Deviation 0.65 |
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.93ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.4295% CI: [-0.224, 0.093]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.07895% CI: [-0.302, 0.016]ANOVA
Secondary
Max QTcB
For each dose, the 95% CIs for the mean difference for the test product versus the reference product were calculated.
Time frame: Baseline through 6 hours
Population: all subjects who received the test and the reference product at the two inhalations dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test B and C vs Reference E and F | Max QTcB | 422.3 ms | Standard Deviation 22.4 |
| Reference Product D | Max QTcB | 422.1 ms | Standard Deviation 23.7 |
| Test Product B | Max QTcB | 430.0 ms | Standard Deviation 23.1 |
| Reference Product E | Max QTcB | 430.2 ms | Standard Deviation 21.4 |
| Test Product C | Max QTcB | 441.0 ms | Standard Deviation 20.5 |
| Reference Product F | Max QTcB | 444.0 ms | Standard Deviation 26.7 |
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.7195% CI: [-3.9, 5.7]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 195% CI: [-4.7, 4.7]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.01695% CI: [-10.6, -1.1]ANOVA
Secondary
Plasma Potassium Level
maximum plasma levels of potassium at 2, 6 or 12 inhalations dose inhalations dose, assessed a multiple times over 6 hours.
Time frame: baseline through 6 hours
Population: subjects who received both the test and reference products at the 2, 6, or 12 inhalations dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test B and C vs Reference E and F | Plasma Potassium Level | 3.82 mmol/L | Standard Deviation 0.19 |
| Reference Product D | Plasma Potassium Level | 3.78 mmol/L | Standard Deviation 0.16 |
| Test Product B | Plasma Potassium Level | 3.76 mmol/L | Standard Deviation 0.2 |
| Reference Product E | Plasma Potassium Level | 3.75 mmol/L | Standard Deviation 0.19 |
| Test Product C | Plasma Potassium Level | 3.63 mmol/L | Standard Deviation 0.24 |
| Reference Product F | Plasma Potassium Level | 3.61 mmol/L | Standard Deviation 0.26 |
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.2695% CI: [-0.03, 0.1]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.9395% CI: [-0.06, 0.06]ANOVA
Comparison: For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated.p-value: 0.4895% CI: [-0.04, 0.08]ANOVA